Abstract The opioid abuse epidemic that is occurring across the United States requires novel strategies to reduce opioid dependence, abuse, and overdose. Pain stemming from acute injury, or diseases such as cancer and AIDS, often require opioid treatments that can produce these adverse effects. Pain from these disorders may be better ameliorated with a poly-drug approach, as opposed to monotherapy with opioids. The growing hesitancy by doctors to prescribe opioids due to adverse effects also comes at a time when access to medical and recreational marijuana is growing. Twenty-nine states have approved medical or recreational marijuana, largely on the basis that cannabinoids (e.g., delta-9-tetrahydrocannabinol, THC) produce pain relief under a variety of conditions. Studies suggest that cannabinoids in combination with opioids reduce the dosage of opioid required to produce pain relief, also known as ?opioid-sparing? effects. Interestingly, cannabinoids have been shown to produce ?opioid-sparing? effects in a synergistic manner, as opposed to combinations of opioids and non- steroidal anti-inflammatory drugs (NSAIDs) that produce analgesic effects in an additive manner. The aims of this project will investigate three aspects of the interaction of cannabinoids and opioids. Specific Aim 1 will examine the opioid-sparing effects of cannabinoids in a well-established thermal antinociception procedure in nonhuman primates. Rhesus macaques will be pretreated with THC prior to assessing the antinociceptive effects of cumulative doses of either fentanyl or buprenorphine. This procedure has particular relevance both for individuals who might be co-abusing opioids and cannabinoids, and those using these combinations under medical supervision. Specific Aim 2 will test the same cannabinoid-opioid combinations in the same nonhuman primates under a procedure that assays the acquisition (learning) of new information as well as the performance of well-rehearsed information. In this way, we can determine if these opioid-sparing analgesic combinations also reduce cognitive-behavioral disruptions of learning and performance behavior. Finally, Specific Aim 3 will examine both the pharmacological mechanisms and precise brain regions in the descending pain pathway that mediate the opioid-sparing effects of the cannabinoids in rats. The periaqueductal gray (PAG) and rostroventral medulla (RVM) contain both cannabinoid and opioid receptors. Therefore, microinjecting selective antagonists for the two major subtypes of cannabinoid (CB) receptor (CB1 and CB2) into the PAG and RVM prior to systemic administration of cannabinoid-opioid combinations, should indicate the involvement of these receptors in the descending pain pathway. Fentanyl and buprenorphine are excellent compounds to study in this circuit because they produce analgesia with different efficacy and selectivity for opioid receptors. In summary, this project has particular relevance to the ongoing opioid abuse epidemic and aims to investigate both mechanistic and clinically-translational applications of the opioid-sparing effects of cannabinoids.